Tetrodotoxin-sensitive voltage-gated sodium channels regulate bladder afferent responses to distension

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a prevalent, chronic bladder disorder that negatively impacts the quality of life for ∼5% of the western population. Hypersensitivity of mechanosensory afferents embedded within the bladder wall is considered a key component in mediating IC/BPS symptoms. Bladder infusion of voltage-gated sodium (NaV) channel blockers show clinical efficacy in treating IC/BPS symptoms, however, the current repertoire of NaV channels expressed by, and contributing to bladder afferent function is unknown. We used single cell RT-PCR of retrogradely-traced bladder-innervating dorsal root ganglia (DRG) neurons to determine the expression profile of NaV channels, and patch-clamp recordings to characterise the contribution of tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) NaV channels to total sodium current and neuronal excitability. We determined the TTX-S and TTX-R contribution to mechanosensitive bladder afferent responses ex-vivo and spinal dorsal horn activation in-vivo. Single cell RT-PCR of bladder-innervating DRG neurons revealed significant heterogeneity in NaV channel co-expression patterns. However, TTX-S NaV channels contribute the vast majority of the total sodium current density and regulate the neuronal excitability of bladder DRG neurons. Furthermore, TTX-S NaV channels mediate almost all bladder afferent responses to distension. In-vivo intra-bladder infusion of TTX significantly reduces activation of dorsal horn neurons within the spinal cord to bladder distension. These data provide the first comprehensive analysis of NaV channel expression within sensory afferents innervating the bladder. They also demonstrate an essential role for TTX-S NaV channel regulation of bladder-innervating DRG neuroexcitability, bladder afferent responses to distension, and nociceptive signalling to the spinal cord.

Pain. 2018 Aug 27 [Epub ahead of print]

Luke Grundy, Andelain Erickson, Ashlee Caldwell, Sonia Garcia-Caraballo, Grigori Rychkov, Andrea Harrington, Stuart M Brierley

Visceral Pain Research Group, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia, 5042, AUSTRALIA., Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, South Australia 5000, AUSTRALIA.